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Rothwell PM, Cook NR, Gaziano JM, et al. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials. Lancet. 2018 Jul 12. pii: S0140-6736(18)31133-4. doi: 10.1016/S0140-6736(18)31133-4.
Area Score
Internal Medicine
Family Medicine (FM)/General Practice (GP)
General Internal Medicine-Primary Care(US)
Oncology - General
Public Health
Cardiology
Abstract

BACKGROUND: A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes.

METHODS: Using individual patient data, we analysed the modifying effects of bodyweight (10 kg bands) and height (10 cm bands) on the effects of low doses (=100 mg) and higher doses (300-325 mg or =500 mg) of aspirin in randomised trials of aspirin in primary prevention of cardiovascular events. We stratified the findings by age, sex, and vascular risk factors, and validated them in trials of aspirin in secondary prevention of stroke. Additionally, we assessed whether any weight or height dependence was evident for the effect of aspirin on 20-year risk of colorectal cancer or any in-trial cancer.

RESULTS: Among ten eligible trials of aspirin in primary prevention (including 117?279 participants), bodyweight varied four-fold and trial median weight ranged from 60·0 kg to 81·2 kg (p<0·0001). The ability of 75-100 mg aspirin to reduce cardiovascular events decreased with increasing weight (pinteraction=0·0072), with benefit seen in people weighing 50-69 kg (hazard ratio [HR] 0·75 [95% CI 0·65-0·85]) but not in those weighing 70 kg or more (0·95 [0·86-1·04]; 1·09 [0·93-1·29] for vascular death). Furthermore, the case fatality of a first cardiovascular event was increased by low-dose aspirin in people weighing 70 kg or more (odds ratio 1·33 [95% CI 1·08-1·64], p=0·0082). Higher doses of aspirin (=325 mg) had the opposite interaction with bodyweight (difference pinteraction=0·0013), reducing cardiovascular events only at higher weight (pinteraction=0·017). Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height (pinteraction=0·0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (pinteraction=0·038). Stratification by body size also revealed harms due to excess dosing: risk of sudden death was increased by aspirin in people at low weight for dose (pinteraction=0·0018) and risk of all-cause death was increased in people weighing less than 50 kg who were receiving 75-100 mg aspirin (HR 1·52 [95% CI 1·04-2·21], p=0·031). In participants aged 70 years or older, the 3-year risk of cancer was also increased by aspirin (1·20 [1·03-1·47], p=0·02), particularly in those weighing less than 70 kg (1·31 [1·07-1·61], p=0·009) and consequently in women (1·44 [1·11-1·87], p=0·0069).

INTERPRETATION: Low doses of aspirin (75-100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin's effects on other outcomes, including cancer, also showed interactions with body size, a one-dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required.

FUNDING: Wellcome Trust and National Institute for Health Research Oxford Biomedical Research Centre.

Comments from MORE raters

Cardiology rater

This can lead to trials to evaluate the protective effects of ASA, but has uncertain value to current practice.

Cardiology rater

As a family medicine physician who regularly counsels patients on the use of aspirin for cardiovascular protection, I was trained with a "one-dose [81mg] fits-all" strategy. This analysis found that higher doses are needed for those weighing over 70kg to gain cardiovascular protection. This information has the potential to change clinical practice; however, the side effects of aspirin must be considered, notably bleeding. The authors only presented relative comparisons of benefit and some relative comparisons of risk across weight categories. Lots of questions remain for its clinical utility. Three of the authors have received fees from Bayer, a maker of aspirin. I hope that other scholars pursue further study of this important topic in primary care and cardiovascular medicine.

General Internal Medicine-Primary Care(US) rater

This type of research has always had some problems, but raises questions that should not be ignored since we tend to ignore weight when prescribing aspirin.

General Internal Medicine-Primary Care(US) rater

This is new, incredibly helpful, and practice-changing. It explains much about variability in outcomes for aspirin use.

Internal Medicine rater

I believe this is new information. I wasn't aware of the controversy.

Internal Medicine rater

I`ve never quite understood the reason why dosing of ASA was not weight/gender related. Although I too used a baby aspirin in adults for primary prevention, at some point I decided that a full ASA was more appropriate (of course not evidence-based) as long as there was no contraindication. This article is important. Weight is important since it affects volume of distribution and therefore the peak and overall clearance of a drug. Why would ASA be different from other drugs? The data indicate that it really is not different, and appropriate weight adjustments to dose are necessary to improve outcomes.

Public Health rater

Interesting results but remains a retrospective study that requires prospective RCT validation before the conclusions "and a more tailored strategy is required" can be fully supported.